1. Field of the Invention
The present invention relates to a novel human collagen protein and a polynucleotide sequence, which encodes the novel human collagen protein. More particularly, it relates to polynucleotides encoding human α1 chain collagen and derivatives thereof.
2. Description of the Related Art
Collagens are structure proteins that participate in the assembly of various kinds of polymers in the extracellular matrix. Collagen polypeptides contain one or more blocks of (Gly-x-y) repeat, in which x represents any amino acid residue, and y frequently represents prolyl or hydroxyprolyl residues. The presence of such sequence repeats allows groups of three collagen polypeptides to fold into triple-helical domains, which are rigid and inextensible.
So far, 20 distinct types of homo-and heterotrimeric molecules, encoded by more than 30 genes, have been identified in vertebrates. These proteins exhibit considerable diversity size, sequences, tissue distribution, molecular composition, and each plays a different structure role in connective tissue.
Within the superfamily of collagens, two categories are classified. The fibrillar collagens include types I, II, III, V, and XI collagen. The triple-helical domains of the proteins polymerize in a staggered fashion to form fibrils. Members of other collagens do not by themselves form cross-striated fibrils, but may be associated with fibrils (FACIT or fibril associated collagens with interrupted triple helices), including types IX, XII, XIV, XVI, and XIX collagen. The structure of these molecules comprises two or more relatively short triple-helical (COL) domains connected and flanked by non-triple-helical (NC) sequences. Type IX collagen is the best-characterized molecule in the members. Studies of transgenic mice with mutations in type IX collagen have been proposed that it acts as molecular bridges between cartilage collagen fibrils and other matrix components, perhaps proteoglycans. The COL domains and the central NC domains of this molecule interact with type II collagen through covalent cross-links to form fibrils. The amino-terminal NC domain has a potential of interacting with other extracellular components. Also, in vitro studies have demonstrated that the N-terminal non-triple-helical domains of type XII and XIV collagen promote contraction of collagen gels. However, the detailed interactions of the bridging hypothesis are not clear.
Collagens are typical mosaic proteins containing a number of shuffled domains. These domains have been classified by sequence similarity in order to characterize their structural and functional relationships to other proteins. This analysis provides an overview of homologies of collagen domains. It also reveals two new relationships: (i) a module common to type V, IX, XI, and XII collagens was found to be homologous to the heparin binding domain of thrombospondin; (ii) the modular architecture of a human type VII collagen fragment was identified. Its N-terminal globular domain contains fibronectin type III repeats located adjacent to a von Willebrand factor type A module. The proposed structural similarities point to analogous subfunctions of the respective domains in otherwise distinct proteins.
Thrombospondin is one of a class of adhesively homotrimeric glycoproteins that mediate cell-to-cell and cell-to-matrix interactions. It is expressed in extracellular matrix, and may have autocrine growth regulatory properties involved in platelet aggregation, embryogenesis, morphogenesis, cell adhesion molecule, major activator of TGFβ1. The von Willebrand factor A (vWF) like domain is the prototype for a protein superfamily and it is found in various proteins including plasma complement factors, integrands, collagens, and other extracellular proteins. Proteins that incorporate vWF domains participate in numerous biological events, such as cell adhesion, migration, homing, pattern formation, and signal transduction.
Collagens are important bio-medical building blocks with the functions of tissue growth, anaplasty, dressing for burn, and wound healing, etc., and the requirements thereof expand largely. Therefore, there is still a need to develop a novel collagen and the derivatives thereof having more therapeutic value and diversity for the various applications.
The present inventors have successfully cloned a novel human α1 chain collagen gene by way of known human expression sequence tag (EST) in combination with bio-informatics and molecular cloning techniques. After comparison of the inventive collagen with the existent 20 collagens, the highest sequence homology is less than 30%, indicating the collagen of the invention is a novel form.
Blood vessels are tubes of endothelial cells surrounded by layers of smooth muscle cells and connective tissue proteins. During development this complex structure forms as a result of biochemical signals between endothelial cells and smooth muscle cells. Sometimes this biochemical communication fails and abnormal blood vessels form. By analyzing gene mutations causing such vascular abnormalities, it can be learned about the signals necessary for normal blood vessel development. In addition, identification of genes responsible for inherited vascular malformations provides a basis for development of rational therapies in the clinical treatment of vascular disorders.